A quantitative-trait genome-wide association study of alcoholism risk in the community: findings and implications
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2011
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Resumo |
BACKGROUND Given moderately strong genetic contributions to variation in alcoholism and heaviness of drinking (50% to 60% heritability) with high correlation of genetic influences, we have conducted a quantitative trait genome-wide association study (GWAS) for phenotypes related to alcohol use and dependence. METHODS Diagnostic interview and blood/buccal samples were obtained from sibships ascertained through the Australian Twin Registry. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed with 8754 individuals (2062 alcohol-dependent cases) selected for informativeness for alcohol use disorder and associated quantitative traits. Family-based association tests were performed for alcohol dependence, dependence factor score, and heaviness of drinking factor score, with confirmatory case-population control comparisons using an unassessed population control series of 3393 Australians with genome-wide SNP data. RESULTS No findings reached genome-wide significance (p = 8.4 x 10(-8) for this study), with lowest p value for primary phenotypes of 1.2 x 10(-7). Convergent findings for quantitative consumption and diagnostic and quantitative dependence measures suggest possible roles for a transmembrane protein gene (TMEM108) and for ANKS1A. The major finding, however, was small effect sizes estimated for individual SNPs, suggesting that hundreds of genetic variants make modest contributions (1/4% of variance or less) to alcohol dependence risk. CONCLUSIONS We conclude that: - 1) meta-analyses of consumption data may contribute usefully to gene discovery; - 2) translation of human alcoholism GWAS results to drug discovery or clinically useful prediction of risk will be challenging, and; - 3) through accumulation across studies, GWAS data may become valuable for improved genetic risk differentiation in research in biological psychiatry (e.g., prospective high-risk or resilience studies). |
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Publicador |
Elsevier |
Relação |
DOI:10.1016/j.biopsych.2011.02.028 Heath, Andrew C., Whitfield, John B., Martin, Nicholas G., Pergadia, Michele L., Goate, Alison M., Lind, Penelope A., McEvoy, Brian P., Schrage, Andrew J., Grant, Julia D., Chou, Yi-Ling, Zhu, Rachel, Henders, Anjali K., Medland, Sarah E., Gordon, Scott D., Nelson, Elliot C., Agrawal, Arpana, Nyholt, Dale R., Bucholz, Kathleen K., Madden, Pamela A.F., & Montgomery, Grant W. (2011) A quantitative-trait genome-wide association study of alcoholism risk in the community: findings and implications. Biological Psychiatry, 70(6), pp. 513-518. |
Palavras-Chave | #Alcohol Drinking/*genetics #Alcoholism/diagnosis/*genetics #Case-Control Studies #Genetic Predisposition to Disease/*genetics #Genome-Wide Association Study/*statistics & numerical data #Genotype #Humans #Phenotype #Polymorphism #Single Nucleotide #Quantitative Trait Loci/*genetics #Residence Characteristics |
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Journal Article |